Browsing by Author "Orallo, Francisco"
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- 5-HT2 antagonist activity of 3-aminomethyltetralonesPublication . Verde, Ignacio; Loza, M.; Castro, Maria Elena; Orallo, Francisco; Fontenla, José Angel; Calleja, José Maria; Ravina, Enrique; Cortizo, L.; Deceballos, M. L.The affinity of four 3-aminomethyltetralones for 5-HT2 receptors is reported, together with their inhibitory activity against serotonin-induced contractions in rat aorta rings stripped of endothelium. Compound 4, which has a p-fluorobenzoyl-piperidine fragment, exhibited activity similar to that of methysergyde.
- Efecto del endotelio sobre las contracciones inducidas por noradrenalina y K+ en aortas de rata genéticamente hipertensa y rata normotensaPublication . Verde, Ignacio; Orallo, Francisco; Gil-Longo, José; Campos, M.Desde que Furchgott (1, 2) descubrió que la presencia de endotelio era imprescindible para la acción relajante vascular de la acetilcolina, han aparecido diversos y variados estudios que demuestran su participación en la relajación provocada por diversos agentes (ATP, serotonina, histamina, ...) (3. 4, 5, 6). Es mas, se han descrito diversos mecanismos en células del endotelio vascular que, al ser activados, pueden estimular la liberación de varios factores endoteliales (7). También se ha demostrado la existencia de una posible disfunción o mal funcionamiento del sistema endotelial en procesos de hipertensión, debido. bien a una dificultad en la liberación de EDRF (endothelium derived relaxing factor)(8), o bien a un aumento en la liberación de EDCF (endothelium derived contracting factor)(9. 10). Con el objeto de confirmar la Influencia de los procesos de hipertensión sobre el estado del endotelio, en el presente trabajo se estudia la posible modulación por el sistema endotelial de las contracciones inducidas por noradrenalina y. CaCI2 (en media despolarizante) en aorta de rata normotensa e hipertensa.
- Efectos de la glaucina sobre las contracciones y el influjo de 45Ca2+ inducido por noradrenalina y K+ en la aorta de rataPublication . Verde, Ignacio; Orallo, Francisco; Loza, M.; Gil-Longo, José; Cadavid, Isabel; Calleja, José MariaLa glaucina es un alcaloide aislado del Glaucium flavum Crantz (1). Se conocen sus efectos sobre varios neurotransmisores centrales (2), su acción neuroendocrina (3), y sus propiedades relajantes musculares atribuidas al efecto inhibidor de la fosfodiesterasa del 3º-5º AMPc aunque algunos autores (4) sugieren que este mecanismo no es suficiente para justificar su efecto relajante a nivel del musculo liso. Con objeto de aportar nuevos datos que contribuyan a esclarecer este mecanismo, en el presente trabajo se realiza un estudio de los efectos de la glaucina sobre las contracciones inducidas por noradrenalina (NA) y K+ en anillos de aorta de rata, y sobre el influjo de 45Ca basal y evocado por los dos agentes vasoconstrictores.
- Efectos del haloperidol y nuevas butirofenonas de sintesis sobre las contracciones inducidas por dopamina en conducto deferente de rataPublication . Verde, Ignacio; Loza, M.; Orallo, Francisco; Cadavid, Isabel; Gato, A.; Calleja, José MariaEI objetivo inicial de este trabajo fué el de estudiar los efectos de dos potenciales agentes neurolépticos (el p-clorobenzoato de pseudotropanol (I) y el p-F-fenil 2-4-o metoxifenilpiperazinometilciclopenitilcetona (II) frente a las contracciones inducidas por dopamina en conducto deferente aislado de rata. Pero, aunque está clara la presencia de dopamina (DA) y noradrenalina (NA) (1), al revisar la bibiografía encontramos datos contradictorios sobre la existencia de receptores postsinápticos específicos para la dopamina en esta preparación. Así, por una parte algunos autores (2) proponen que la DA activa una población de receptores postsinápticos que se diferencian de los activados por la NA, basándose en el hecho de que encontraron valores de pA2, distintos para la NA y para la DA utilizando varias antagonistas. Por otro lado, otros autores (3, 4) proponen que tanto la NA como la DA activan una población homogénea de receptores en vaso deferente de rata. Para demostrarlo utilizan una solución de Krebs especial a la que añaden inhibidores de la recaptaci6n, bloqueantes de receptores beta-adrenérgicos, y además modifican el tiempo de preincubación del antagonista. En nuestro trabajo estudiamos el efecto del haloperidol frente a las contracciones inducidas por NA y DA en ausencia y en presencia de inhibidores de la recaptaci6n neuronal (cocaina), extraneuronal (estradiol), y de un bloqueante beta adrenérgico (propranolol); y el de los dos potenciales neurolépticos (compuestos I y II) frente a las contracciones inducidas por dopamina en condiciones normales.
- Effects of platelet-activating-factor on contractions and 45Ca2+ influx induced by noradrenaline and potassium in rat rubbed and intact aorta - comparison with its hypotensive effect in anesthetized normotensive ratsPublication . Verde, Ignacio; Orallo, Francisco; Loza, Isabel; Alzueta, A. F.; Campos,Manuel; Freire-Garabal, ManuelIn order to clarify the mechanism of hypotensive activity of platelet activating factor (PAF), the effects of this drug on blood pressure in anaesthetized normotensive rats, on KCl- and noradrenaline-induced 45Ca uptake and contractile responses in rat aorta rings with and without endothelium were studied. PAF (3 micrograms kg-1, i.v.) showed long-lasting hypotensive effects in anaesthetized normotensive rats accompanied by a significant increase in heart rate. PAF (0.1-10 microM) did not relax the contractions induced by noradrenaline (10 microM) or K+ (60 mM) in rubbed or intact rat aorta. PAF did not affect the basal uptake of 45Ca2+ nor that induced by the two vasoconstrictor agents. In experiments in a calcium free medium, PAF (10 microM) had no effect on the noradrenaline- (10 microM) induced contractions. These results suggest that the hypotensive activity of PAF in normotensive anaesthetized rats is not due to a direct effect on rubbed and intact rat aorta rings (acting within the cell or blocking Ca2+ influx through L-type transmembrane calcium channels).
- Effects of trans- and cis-resveratrol on Ca2+ handling in A7r5 vascular myocytesPublication . Verde, Ignacio; Campos-Toimil, Manuel; Elies, Jacobo; Alvarez, Ezequiel; Orallo, FranciscoAlthough the natural polyphenol resveratrol posses a direct vasorelaxant effect, its effects on cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) in vascular cells remain still unclear. Here, we have investigated the effects of the isomers trans- and cis-resveratrol on agonist- and high-K(+)-induced [Ca(2+)](i) increases and on voltage-activated transmembrane Ca(2+) fluxes using imaging and patch-clamp techniques in vascular A7r5 myocytes. Arginine vasopressin (AVP) or angiotensin II caused a biphasic increase in [Ca(2+)](i) that was reduced by preincubation with trans-resveratrol and cis-resveratrol. Both isomers also reduced the agonist-induced increase in [Ca(2+)](i) in absence of extracellular Ca(2+). In high-K(+) Ca(2+)-free solution, reintroduction of Ca(2+) caused a sustained rise in [Ca(2+)](i) that was reduced by preincubation with trans-resveratrol or cis-resveratrol. When the isomers were applied during the plateau phase of the agonist- or the high-K(+)-induced response, a biphasic change in [Ca(2+)](i) was observed: a transient reduction of the plateau (<5 min) followed by an increase (>10 min). Finally, trans-resveratrol and cis-resveratrol inhibited voltage-dependent L-type Ca(2+) currents (I(Ca(L))). In conclusion, resveratrol isomers exert a dual effect on [Ca(2+)](i) handling in A7r5 myocytes: 1) a blockade of I(Ca(L)) and 2) an increase in [Ca(2+)](i) by depletion of intracellular Ca(2+) stores (which interferes with the agonist-induced release of intracellular Ca(2+)) and influx of Ca(2+), mainly due to activation of capacitative Ca(2+) entry, although other Ca(2+)-permeable channels are also involved. Taken together, these effects may explain, in part, the endothelium-independent vasorelaxant effects of resveratrol in rat aorta.
- Modulacion por el endotelio de las contracciones induzidas por distintos agonistas alfa-adrenérgicos en la aorta de rataPublication . Verde, Ignacio; Loza, M.; Gil-Longo, José; Campos, M.; Orallo, Francisco; Calleja, José MariaDesde que Furchgott (5), (6) descubri6 que la presencia de endolelio es imprescindible para la acción relajante vascular de la acetilcolina, han aparecido múltiples estudios que demuestran que las células endoteliales pueden desempeñar un papel decisivo CD la modulaci6n de determinados procesos biológicos, como por ejemplo, el tono vascular (1), (9), (13), (15) Y 105 efectos de distintos fármacos (1), (14). Es más, se ha descrito la presencia de receptores alfa2 CD e1 endotelio vascular cuya activación puede estimular la liberaci6n de EDRF (3), (4). Con el objeto de confirmar la presencia de dichos receptores, CD el presente trabajo se estudia la posible modulaci6n por el endotelio de Las contracciones inducidas por distintos agonistas alfaadren6rgicos en la aorta de rata.
- Pharmacological study of several effects of hydralazine in the bisected rat vas deferensPublication . Verde, Ignacio; Campos-Toimil, Manuel; Orallo, Francisco; Gil-Longo, José; Loza, Isabel; Fernandez-Alzueta, AlejandroWe have studied several effects of hydralazine in the bisected rat vas deferens. Hydralazine produced a shift to the left of the concentration-response curve for noradrenaline, with potentiation of the maximal response in both portions of the vas deferens. In contrast it caused a shift to the right of the concentration-response curve for noradrenaline in preparations pretreated with cocaine (inhibitor of catecholamine neuronal uptake), and of the curve for methoxamine and for CaCl2 (in depolarizing medium with K+ 55 mM), in all cases with depression of the maximal response. Hydralazine enhanced the contractions induced by noradrenaline in Ca2+-free medium, except in the presence of cocaine. It had no effect on [3H]noradrenaline neuronal uptake into noradrenergic neurons of the vas deferens, nor did it affect basal or K+-induced 45Ca2+ uptake. These results suggest that hydralazine potentiates the contractions elicited by noradrenergic by a mechanism other than blockade of the neuronal uptake of this catecholamine. Our results also suggest that the inhibition by hydralazine of the contraction elicited by Ca2+ (in Ca2-free depolarizing high-K+ 55 mM solution) and by methoxamine is not due to an action on voltage-dependent Ca2+ channels, but may reflect an intracellular site of action.
- Pyridazine derivatives. XI: Antihypertensive activity of 3-hydrazinocycloheptyl[1,2-C]pyridazine and its hydrazone derivativesPublication . Gil-Longo, José; Laguna, Maria de los Reyes; Verde, Ignacio; Castro, Elena; Orallo, Francisco; Fontenla, Jose A.; Calleja, José Maria; Ravina, Enrique; Terán, Carmen3-Hydrazinocycloheptyl[1,2-c]pyridazine (4) and its hydrazone derivatives 3-[N1-(isopropylidene)]hydrazinocycloheptyl[1,2-c]pyridazine [correction of hydrazinocyclohexyl] (5) and 3-[N1-(isobutylidene)]hydrazinocycloheptyl[1,2-c]pyridazine (6) were prepared, and their activity against genetic, neurogenically-induced, and deoxycorticosterone acetate -NaCl-induced hypertension was found to be at least as great as that of hydralazine. The results of studying vasorelaxation of rat aorta by 4 and hydralazine suggest that both these compounds owe their antihypertensive activity to direct relaxation of vascular smooth muscle.
- Role of the endothelial system in Bay-K-8644 enantiomer and nifedipine vasomodulator action in rat aortaPublication . Verde, Ignacio; Gil-Longo, José; Orallo, Francisco; Campos, Manuel; Calleja, José MariaThe potential importance of the endothelial system in regulating the effects of (−)-Bay K 8644 (0.1 μM), (+)-Bay K 8644 (0.1 μM) and nifedipine (10 nM) on resting tension, on contractile responses to noradrcnaline (NA) and Ca2+ (in a Ca2+-free high-K+ solution), and on basal, NA-induced and K+-induced 45Ca2+ uptake, was investigated in rat aorta rings. Mechanical removal of endothclium considerably potentiated the contractile response induced by NA in standard medium and by Ca2+ in Ca2+-free high-K' (15 mM) medium, but did not modify the response induced by Ca2+ in Ca2+-frcc high-K+ (55 mM) medium or by NA in Ca2+-free medium. Furthermore, the basal 45Ca2+ uptake and that induced by NA (10 μM) or KCl (15 and 55 mM) were similar in endothelium-rubbed and intact rings. (−)-Bay K 8644 (0.1 μM) shifted the NA and Ca2+ concentration-response curves to the left with potentialion of the maximal contraction. However, (+)-Bay K 8644 (0.1 μM) and nifedipine (10 nM) caused a shift to the right, with depression of the maximal contraction. The NA concentration-response curves, and those of Ca2+ in Ca2+-free high-K+ (55 mM) medium, were affected by the drugs to similar extents, and were not modified by the presence or absence of endothelial cells. The drugs tested did not affect resting tension. Basal 45Ca2+ uptake was not modified by either nifedipine or the Bay K 8644 enantiomers. On the other hand, (−)-Bay K 8644 increased with equal effectives both NA- and KCl-induccd 45Ca2+ uptake, whilst (+)-Qay K 8644 and nifedipine inhibited both uptakes. The presence or absence of endothelium did not modify these effects. These results suggest that, in rat aorta, the endothelial system does not modulate either the agonist effect of (−)-Bay K 8644 or the antagonistic effects of (+)-Bay K S644 and nifedipine. Furthermore, our data indicate that the effects of Bay K 8644 enantiomers and nifedipine on the contractile responses and 45Ca2+ uptake elicited by NA and high-K+ (55 mM) solutions are similar.